Probably the single factor most dramatically increasing a woman's risk of breast cancer is the presence of the disease in her immediate family, especially if more than one relative has had breast cancer, or if the relative was affected bilaterally or at a young age. However, we do not know if this increased risk is due to social, dietary, or environmental factors that predispose the family to breast cancer or to inherited factors that increase susceptibility to the disease. The objective of this project is to unravel the genetic and environmental contributions to breast cancer. We will study (1) exceptional extended kindreds at very high risk of breast cancer and (2) 2500 four-generation families, each identified through a cancer patient or control from a population-based registry. In the approximately 25 high-risk kindreds, we will use segregation analysis and linkage analysis to DNA polymorphisms to identify and map genes that increase susceptibility to breast cancer. We will determine whether inherited susceptibility to breast cancer is chromosomally linked to polymorphisms in oncogenes, MMTV-related sequences, or other DNA sequences potentially related to breast carcinogenesis. In addition, we will screen polymorphic DNA markers randomly spaced throughout the genome for linkage to breast cancer susceptibility in each high-risk kindred. We suspect different genes are involved in different families, and hope to identify these genes for further study. In the population-based sample of families, the goal is to elucidate epidemiologic and genetic models for inheritance of susceptibility to breast cancer, estimate the proportion of breast cancer among American women influenced by genetic susceptibility, and determine environmental and cultural factors that influence the expression of genetic susceptibility. Not only are these results of immediate value for young women in high-risk families, but they are also applicable to etiology of breast cancer in general, in that high-risk families serve as a model for breast cancer in the population as a whole. That is, the genes that are altered in high-risk families exist as normal sequences in all women. In breast epithelial cells, these genes are subject to attack by environmental carcinogens. Therefore, changes in these sequences may cause breast cancer in women who have no inherited susceptibility. Thus, identifying genes important for inherited breast cancer may reveal genes crucial to environmentally induced breast cancer as well.